The rupture risk factors of mirror intracranial aneurysms: A systematic review and meta-analysis based on morphological and hemodynamic parameters

Objective Intracranial aneurysms (IAs) are a prevalent form of vascular disease that can lead to fatal outcomes upon rupture. Mirror intracranial aneurysms (MIAs) are a specific type of multiple aneurysms situated symmetrically on both sides of the parent arteries. The factors contributing to the risk of MIA rupture, based on morphological and hemodynamic parameters, are currently controversial. Thus, we conducted a systematic review and meta-analysis to investigate the risk factors for MIA rupture. Methods The study performed an electronic search of Chinese and English databases, including China national Knowledge Infrastructure (CNKI), WanFang, VIP, PubMed, Embase, Web of Science, Scopus, and the Cochrane Library databases, and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The morphological parameters (IA size, aspect ratio [AR], size ratio [SR], bottleneck factor [BNF], height-width ratio [HWR], irregular shape) and hemodynamic parameters (wall shear stress [WSS], low WSS area [LSA], oscillatory shear index [OSI]) were analyzed for their significance in determining the risk of MIA rupture. Results The analysis comprised 18 retrospective studies involving 647 patients, with a total of 1294 IAs detected, including 605 ruptured and 689 unruptured. The meta-analysis revealed that IA size, AR, SR, and irregular shape exhibited significant differences between the ruptured and unruptured groups, but HWR did not. In terms of hemodynamic parameters, WSS, OSI, and LSA were found to have significant differences between the two groups. Conclusions Our results demonstrate that larger IAs, higher AR, SR, and BNF are associated with a higher risk of rupture in patients with MIAs, regardless of their location. there is no significant difference in HWR between the ruptured and unruptured groups. These preliminary findings offer valuable insights for clinical decision-making and a more comprehensive comprehension of the current MIA status. Nevertheless, larger and multi-center studies are indispensable for corroborating these findings. Systematic review registration: https://www.crd.york.ac.uk/prospero/ identifier: CRD42022345587.


Introduction
Intracranial aneurysms (IAs) are a prevalent vascular disorder, and if they rupture, can lead to fatal outcomes. The estimated prevalence of IAs in adults ranges from 2% to 3% [1]. Although the rupture rate of IAs is relatively low, between 0.95% to 1.6% [2, 3], sudden rupture can cause severe subarachnoid hemorrhage (SAH), which results in high mortality and severe complications, accounting for 50-60% and 30-40%, respectively [4]. Given that surgical interventions, such as coiling and clipping, carry the risk of complications, it is crucial to weigh the risk of rupture against the potential complications when making treatment decisions for unruptured aneurysms [5]. Therefore, identifying the rupture risk factors for IAs is crucial to aid in making appropriate treatment decisions.
The exact mechanism behind IA rupture is not fully understood and is considered to be complex. Morphology and hemodynamics have been identified as risk factors for IA pathogenesis, progression, and rupture [6][7][8]. However, previous studies exploring the morphological or hemodynamic risk factors for IA rupture have produced conflicting and controversial results [9][10][11][12]. For example, Cebral et al. [11] found a link between high wall shear stress (WSS) and ruptured IAs, while Xiang et al. [7] suggested that low WSS area (LSA) and high oscillatory shear index (OSI) were associated with aneurysm rupture. These differences could be attributed to variations in individual factors and aneurysm locations.
Mirror intracranial aneurysms (MIAs) are a unique type of multiple aneurysms located in the same position on each side of the parent arteries. The rupture of MIAs occurs when one aneurysm ruptures while the other remains intact. MIAs provide an ideal model for studying the parameters associated with rupture. However, the lack of agreement on the rupture-related risk factors for MIAs has limited the ability to make informed treatment decisions. In view of this, we conducted a systematic review and meta-analysis based on morphological and hemodynamic parameters to investigate the rupture risk factors of MIAs. To the best of our knowledge, this is the first meta-analysis to summarize and analyze the rupture risk factors of MIAs.
Population: Patients diagnosed with Intracranial Aneurysms (MIAs). Intervention: Computational fluid dynamics (CFD) analysis of hemodynamics and assessment of morphology using a 3D-DSA workstation. Comparisons: Comparison between the ruptured and unruptured groups. Outcomes: morphological parameters, which include aneurysm size, aspect ratio (AR), size ratio (SR), bottleneck factor (BNF), height-width ratio (HWR), irregular shape, and hemodynamic parameters (WSS, OSI, LSA). The definitions for these parameters can be found in S2 Table. Search strategy In order to identify relevant articles, a systematic search of both Chinese and English databases was conducted. Chinese databases including China national Knowledge Infrastructure (CNKI), Wan Fang, and VIP, as well as English databases such as PubMed, Embase, Web of Science, Scopus, and the Cochrane Library, were searched. Clinical trial registry centers, including clinicaltrials.gov and WHO-ICTRP, were also screened. The search was conducted from the inception of the databases to the end of August 2022 by three reviewers (Huang YW, Yin XS, and Wang XY), using controlled vocabulary (MeSH terms and Emtree) and keywords. The search strategy included the keywords "mirror" AND ("intracranial aneurysm" OR related terms) to ensure all relevant studies were identified. The detailed search strategy is provided in S3 Table. Inclusion and exclusion criteria In this study, two independent reviewers (Huang YW and Yin XS) assessed all potential articles to determine their compliance with the inclusion and exclusion criteria. Only peerreviewed medical journal articles that included patients with MIAs with complete morphological or hemodynamic parameters were considered for inclusion. The comparison of interest was between the ruptured group and the unruptured group, and the outcome measures included morphological parameters (such as the size of the aneurysm, AR, SR, BNF, HWR, and irregular shape) and hemodynamic parameters (WSS, OSI, LSA). Articles such as case reports, reviews, notes, meta-analyses, editorials, letters to the editor, commentaries, and conference abstracts were excluded from this study.

Data extraction
The extracted data from the included studies were independently reviewed by two reviewers using standardized tables. The following information was extracted: Essential characteristics such as first author, year of publication, country, study design, and number of participants; participant characteristics such as age, gender distribution, location of MIAs, focus of study, modeling of MIAs, hemodynamic parameters, and morphological parameters; and any other relevant data.

Risk of bias assessment
The potential risk of bias in each study was evaluated using the Newcastle-Ottawa Scale (NOS) tool [15], which assigns a maximum score of nine points. Studies with a score of greater than six points were considered to be of high quality. The evaluation was independently performed by three reviewers (Huang YW, Yin XS, and Li Li ZP), and any disagreements were resolved through group discussions among investigators when necessary.

Statistical analysis
In order to compare outcomes between ruptured and unruptured groups of MIAs, we conducted a meta-analysis and computed the mean differences (MDs) and 95% confidence intervals (CIs) for continuous variables, and the odds ratios (ORs) and 95% CIs for dichotomous variables. In instances where parameters were reported as median (interquartile), we estimated the mean and standard deviation using sample size, median, range, and interquartile range, following the methods recommended by Luo et al. [16] and Wan et al [17]. The website https://www.math.hkbu.edu.hk/˜tongt/papers/median2mean.html was used for this purpose. We used the random-effects model of DerSimonian and Laird to account for clinical heterogeneity during meta-analysis [18]. We deemed a p-value less than 0.05 to be statistically significant, and assessed the degree of heterogeneity between studies using the Cochrane Q test, with a p-value less than 0.1 or I 2 greater than 50% indicating significant heterogeneity [19]. Statistical analyses were performed using Review Manager software version 5.3.3.

Result of literature search and characteristics of eligible studies
We conducted an exhaustive search of the literature and identified 607 relevant records. Among these, we subjected 23 articles to full-text evaluation, and ultimately included 18 studies in our systematic review and meta-analysis [8, 20-36]. We excluded five articles (one abstract, one on an unrelated topic, one with duplicate data, one with insufficient data, and one systematic review) during the screening process, as shown in the PRISMA flowchart (Fig  1). The  All studies indicated that the prevalence of MIAs was higher in females than males. We present a summary of our systematic review in Table 1.
In summary, the size of IAs, AR, SR, BNF, irregular shape, WSS, OSI, and LSA were identified as significant risk factors for MIA rupture, with the exception of HWR. However, our results displayed substantial heterogeneity, which persisted even after removing studies individually. The heterogeneity may be due to variations in study design, measurement tools, and other factors.

Risk of bias assessment
All of the included studies were assessed retrospectively and evaluated using the Newcastle-Ottawa Scale (NOS), with a mean score of 6.78 stars and a standard deviation (SD) of 0.78 stars. The methodological quality of the studies is summarized in S4 Table, revealing a low risk of bias in the areas of selection bias, detection bias, and reporting bias. A funnel plot analysis was conducted to assess the possibility of publication bias, and the relevant results are presented in S1 Fig.

Discussion
The rupture risk of intracranial aneurysms (IAs) is determined by both morphological and hemodynamic factors. While many studies have investigated the relationship between these factors and the rupture of microintracranial aneurysms (MIAs), there has been a significant focus on the aneurysm size, which is not a comprehensive approach. To address this limitation, the concept of size ratio (SR) has been introduced as a promising morphological  Therefore, further research that considers these factors is needed to gain a more comprehensive understanding of the relationship between IA morphological and hemodynamic factors and rupture risk. The study by Ujiie et al.
[44] defined AR as the ratio of the maximum vertical height (H p ) to the average neck diameter (D neck ) of an aneurysm. According to this and other studies, higher AR values were found to be independently associated with an increased risk of aneurysm rupture. As the AR increases, the height of the aneurysm increases or the neck becomes smaller, which can lead to complex flow patterns and slow circulation inside the aneurysm. These changes can trigger inflammation in the aneurysm wall and increase the risk of rupture [44, 45]. The study by Li et al. [21] found that SR was the sole morphological characteristic In terms of hemodynamics, the WSS is crucial to the formation, progression, and rupture of IAs. WSS is a frictional force created by the viscous flow of blood on the vessel surface, and it regulates gene expression and cellular functions in vessel walls via mechanoreceptors in endothelial cells. Low WSS is associated with the degeneration of these cells and can lead to inflammation and an increased risk of rupture. The LSA was found to be another factor related to the rupture risk of IAs, with higher LSA values being associated with a higher risk of rupture. Lu et al.'s study showed that lower WSS, higher LSA, and higher OSI were observed in the ruptured group [20]. However, the study had a small sample size, and additional studies are needed to confirm these findings. Other studies have shown that higher LSA values and lower WSS values are associated with an increased risk of IA rupture, both with and without bifurcations [22,23]. Another study found that factors such as lower WSS, higher LSA, and higher AR were all associated with IA rupture and that hemodynamics played a crucial role in determining the rupture status of an aneurysm [22]. In 2005, a study exploring both morphological and hemodynamic characteristics showed that higher AR and LSA were reliable indicators for IA rupture. Additionally, SR, HWR, and BNF were found to be higher in ruptured IAs compared to unruptured IAs, with a significant difference between the two groups [23]. A study involving 56 pairs of MIAs found a correlation between larger IAs and lower WSS with IA rupture [26]. Despite these findings, the author suggests that multi-center and multi- The implications of this study's findings for clinical practice are substantial. Our results indicate that various morphological and hemodynamic parameters of mirror intracranial aneurysms, such as size, AR, SR, irregular shape, WSS, OSI, and LSA, can be utilized as predictors of rupture risk. This valuable information can assist healthcare providers in making informed decisions regarding the management and treatment of these aneurysms, ultimately leading to improved patient outcomes. By taking into account the specific factors that contribute to rupture risk, medical professionals can develop tailored treatment plans and preventative measures, thus reducing the incidence of life-threatening ruptures. Additionally, our study's results can guide the development of new screening and monitoring protocols for mirror intracranial aneurysms, facilitating earlier detection and treatment. Overall, these findings have the potential to significantly impact clinical practice and improve patient care.  Our meta-analysis provides a comprehensive and systematic review of existing studies on the morphological and hemodynamic parameters of MIAs, yielding three key findings. Firstly, larger IAs, higher AR, SR, and BNF are associated with a higher risk of rupture in patients with MIAs, regardless of their location. However, we found that the HWR did not significantly differ between the ruptured and unruptured groups. Secondly, most parameters are multi-faceted factors that accurately represent the status of MIAs. Thirdly, the urgent need for further research into hemodynamic factors is highlighted as they have been shown to have severe and devastating consequences. By assessing the morphological and hemodynamic parameters of MIAs, neurosurgeons can identify potential adverse outcomes, such as life-threatening ruptures, earlier. Nonetheless, it is important to acknowledge some limitations of our study, including the predominantly retrospective nature of the analyzed studies, small sample sizes, and a limited geographical representation. Despite these limitations, our findings could be valuable for clinicians in making treatment decisions for patients with MIAs.

Limitations
It is important to acknowledge the limitations of our meta-analysis. Firstly, the retrospective nature of the majority of the studies analyzed, rather than randomized controlled trials, may affect the strength of our findings. Moreover, some studies had small sample sizes, ranging from 8 to 99 participants. Secondly, the vast majority of the studies (17 out of 18) were conducted by Chinese researchers, highlighting the need for more studies from diverse populations and countries. Finally, the high degree of heterogeneity among the studies analyzed may affect the generalizability of our results. Nevertheless, despite these limitations, we believe that our preliminary findings may still provide clinicians with valuable insights for treating patients with MIAs. Further studies with larger sample sizes and a more diverse population are warranted to validate our results.

Conclusion
Our results demonstrate that larger IAs, higher AR, SR, and BNF are associated with a higher risk of rupture in patients with MIAs, regardless of their location. there is no significant difference in HWR between the ruptured and unruptured groups. These preliminary findings offer valuable insights for clinical decision-making and a more comprehensive comprehension of the current MIA status. Nevertheless, larger and multi-center studies are indispensable for corroborating these findings.
Supporting information S1